XXplored Podcast – Why Sex Matters & What we’ve Ignored in Brain Ageing

Voice Over:

Welcome to XXplored Women's Brain Health, a Dementia Researcher podcast exploring the many factors that shape women's brain health across the lifespan.

Dr Laura Stankeviciute:

Hello, I'm Dr. Laura Stankeviciute, your host for the series XXplored Women's Brain Health, where we unpack how sex and gender shape the brain and why women's brain health deserves a conversation of its own. My research focuses on the role of sleep and healthy ageing and Alzheimer's disease, and I'm particularly interested also in how sex differences including hormonal fluctuations during the perimenopause, influence sleep patterns and interact with Alzheimer's disease biomarkers to shape disease progression.

That's why I'm really excited today to be launching this podcast and doing so during the Menopause Awareness Month. Today it's the beginning of the podcast and we're going to lay the foundation for the whole series, asking why sex matters in brain health, and why that question has been overlooked for too many years. We'll start with a dive into the biology of what science now tell us about how biological sex and gender shape the brain across the lifespan. But we'll then move on to the historical blind spots in biomedical research, including how and why women were often considered or labelled too complex to study.

And finally, we will explore where science, care, and the opportunities for change stand today. So, joining me today are two extraordinary researchers who have been leading the charge in this field. It is real pleasure to introduce Professor Liisa Galea, who is a leading neuroscientist whose work has really fundamentally advanced our understanding how sex hormones influence brain plasticity, cognition, mood, and vulnerability to disease across the female lifespan. She's a tri-living family chair in women's mental health at the Centre for Addiction and Mental Health in Toronto, where she also leads the Women's Health Research Cluster.

And the other speaker who's my pleasure to introduce is Dr. Maria Teresa Ferretti. She is a Neuroscientist by background and also a co-founder of the Woman's Brain Project. She's a passionate advocate for sex aware precision medicine in brain health. You may have seen her as a TED speaker, a book author, and driving force behind efforts to make neuroscience more inclusive. So welcome both of you.

Professor Liisa Galea:

Thank you so much for having us.

Dr Maria Teresa Ferretti:

Thank you. And hi, everybody.

Dr Laura Stankeviciute:

So, before we actually move to the questions around this topic, I would love to actually hear a bit about your personal stories, and what were the first questions that sparked your interest and laid the foundation to come into this topic of research?

Professor Liisa Galea:

I guess I would say that I describe myself as a neuroscientist by training, but a women's health advocate by need, by desire, by calling, I guess. And I think I first started getting interested in this because I was told at a really young age I couldn't do something because I was a girl. And I remember being really incensed by that and wondering why that possibly could be. And my parents, bless them, were very much like, "You can do whatever you want." And that sort of gave me the courage to question it when people told me I couldn't do something.

Dr Laura Stankeviciute:

That's a very strong message. And it's beautiful that you had those support figures in your life that made you where you are actually right now. So, thanks to your parents. And what about you, Maria?

Dr Maria Teresa Ferretti:

So, I'm also a neuroscientist by training. So that part, and if I think how I got into this line of research and then advocacy and then it became really a passion of mine. I was doing basic research. I was working with my mice, doing my PhD, my postdoc, so lab coat, pipette, mouse, and I was using both male and female mice, full disclosure, but never occurred to me the idea of stratifying by sex.

And I think I would've blissfully continued like that if I hadn't started during my postdoc to do a little bit of clinical research to collaborate with a memory clinic in Zurich and to start having access to clinical samples. And that's where the heterogeneity of the samples and the data really hit me compared to mouse model, always field of Alzheimer's, right? So, these samples were so heterogeneous, much more obviously these are human beings, and one of the things that was driving this variability was obviously sex.

We had a lot more samples from women than men. And that's when it hit me the first time, why are there more women? What is behind this? What is the reason? And I would start asking around, and nobody really knew, and nobody care. And because I'm a little bit of a stubborn person, I was like, "No, this is unacceptable. We must find an answer." This is so interesting biologically, there must be a reason, and we might find something just insightful and might lead to some discovery.

So, this is really how it started for me as an intellectual curiosity. And then working in it, like Liisa said, this really became a passion because I realised how much we were missing, how much this is a gap, and how much integrating the sex and gender insights can actually have an impact in the life of patients with dementia and with a number of other diseases. So, I hope some of the people listening to this podcast will have a similar trajectory.

Dr Laura Stankeviciute:

Yeah, it probably is. And obviously we see that sometimes out of the lack of something because we don't have something, we then push ourselves, dive into that area and actually create the amazing science and insights that you have both been doing because we did not have many answers before.

Professor Liisa Galea:

Yeah, I will just say also, Maria Teresa, like I had the same kind of experience on almost exactly the same as you described, although I actually started in human research first. But for me it was also going to the literature and just asking, "Well, what do we know about what happens in females or women compared to what happens in men and males?" It still to this day isn't enough research when you go and look at, it's troubling.

Dr Laura Stankeviciute:

So, to really ground maybe our conversation and for why are we even talking about sex difference in brain health and in ageing and in other different neurological and immune conditions, why do we have to talk about this? Well, I would really like to start with that and ask where do you think in terms of biological underpinnings, females and males differ? What does science tell us about that? So, Liisa, maybe you could take that?

Professor Liisa Galea:

Say it's at every single level. If you're talking about what the biological differences we might see in the brain, for example, we see it on a structural level. So that just means how many particular brain cells are packed into a certain area. So sometimes people will talk about the volumes of different structures. We see it in that, we see it in the white matter, which is just the highways between these, the way that the neurons communicate through these highways, white matter, and we see it in the tiny little receptors. We see it in the immune cells that are in the brain. We see it in virtually everything. We see that hormones themselves can influence all of these. We see that chromosomes can influence all of these. So, whether you're an XX or an XY or an X-naught or an XXY, there are just so many differences. It's hard to sort of summarise them all. Although I would say that there is not one sex that has many more brain areas that are larger than another sex.

It's true that men's head sizes are bigger, so in general, their brains are bigger. But even when you compensate for that, you still see certain areas that are larger in females and males, for example. And hormones influence it, I think I said that already. Hormones influence, genetics influence, experience influence these structures and connectivity as well.

Dr Laura Stankeviciute:

Yeah. So, we obviously mentioned a constellation of factors and changes that are different between the sexes. And you just dropped the word that I wanted to pull out, which is hormones. So how do the reproductive hormones then shape women's brain across the lifespan? Could you just walk us through this period from the beginning to our old age?

Professor Liisa Galea:

Yes. Well, how don't they shape it, I guess let's say. Honestly, again, we don't have, I think we did a study a few years ago that suggested only 3% of studies have actually looked at females only, asked the questions on women's brain health across the lifespan. That was a number of different journals in neuroscience and psychiatry. So, we don't have enough information, but our hormones are shaping our brains throughout life. There was sort of this old idea that it was only early on and when you went through puberty, which was sort of the end of it all. But I would say that that's not really quite true.

We know that these hormonal transitions that females in particular have. I mean, I know males and females both go through puberty, but puberty, the menstrual cycle, pregnancy, postpartum, and perimenopause and menopause, there are very dramatic fluctuations in hormones. And I don't want to say that men don't have these. They also have these; it's in different sort of absolute values. Even with pregnancy, obviously they're not getting pregnant, but when they become a father, they're actually, testosterone levels change as well. So does prolactin, so does these other hormones like oxytocin. So, I don't want to get too technical, but just to say that these, anytime you see a dramatic hormonal fluctuation throughout the lifespan, you can expect to see not just body changes, but also brain changes as well.

Dr Laura Stankeviciute:

Yeah, and I also like that you mentioned males because sometimes I feel like we are obviously advocating for the woman's research because it has been on the sidelines for a long time, but male's biology is also important in their own cognitive ageing trajectories. So, I love that you also acknowledge that part. And given that we've talked a little bit about the differences and obviously what the biology means for different infliction points in terms of vulnerabilities, I would like to bring attention to the topic that brings us all together, which is ageing research and Alzheimer's risk for women. So, I would like to now give a question and time for Maria Teresa, and actually explain a little bit why do we think that sex differences are explaining this higher vulnerability for females?

Dr Maria Teresa Ferretti:

Yeah, this is still an open question, and even what we mean by vulnerability to females is an open point. So, we always talk about higher prevalence, more women than men are affected by Alzheimer's. When we measure risk is a higher lifetime risk over the entire lifetime. And the reasons for that are for sure multiple. And I don't think we have a definitive answer. When I first asked this question as I told you, the answer was that women live longer, and so that's why they get more dementia. So, let's clear that out of the way because yes, indeed it's true that women live a little bit longer, but that cannot explain the higher incidence and especially prevalence. So, there must be something else.

There are a number of directions that research has taken that maybe I can highlight. For sure, we have seen, we know now thanks to the research in the past 10 years, that menopause, since we are talking about this now. So, the ageing process in women and even before ageing, the menopausal transition is a window of vulnerability for women to develop, especially Alzheimer's type of dementia.

So biologically, we are starting to understand that not in all women, but in some women, in many of them, when our hormonal levels are starting to fluctuate and change, this opens a vulnerability to the deposition of tau especially. So, one of these toxic proteins that accumulates in Alzheimer's, and this makes these brains then more vulnerable also to amyloid pathology and then cognitive decline. So, there is definitely something that happens biologically that is linked to our hormones, unfortunately is not an easy correlation because it's not just the drop of oestrogen. We have tested this hypothesis; it doesn't exactly work like that. So, we are just starting to understand what is happening precisely at the molecular level. But for sure there is a biological component.

And then of course, I mean there are a number of things that we could mention. There is the selective survival hypothesis. So, the idea that men tend to die earlier, especially of cardiovascular diseases. Women tend to survive two cardiovascular events but then carry on in later years a higher risk for dementia.

And I think we should just not forget the fact that there are a number of lifestyle-related risk factors that are different between men and women. This is one of the topics I'm most passionate about, the prevention of dementia, the possibility to actually reduce our risk just changing our lifestyle. And this modifiable risk factors for dementia are so different among men and women, and many of them affect more women than men if I think about lower education or depression. But some of them just affect differently. So, for instance, again, cardiovascular hypertension, risk factors in midlife, there are risk factors for both men and women, but confer a higher risk to women.

So, there is also this, and then women have sex-specific risk factor, like early menopause. So, there is all in all a number of, I think biological reason and then also gender-related reasons. So, the whole socioeconomic environment in which women age, we have to remember that women tend to live more years in poverty after pension. So, it's not just biology. There are also societal aspects, but there are different, definitely many, many areas that we still need to explore to understand why we have these differences at the level of number of patients.

Dr Laura Stankeviciute:

Thank you so much for this great overview and actually just highlighting how complex it all is. And then when we see these differences both in terms of brain structural and functional changes between men and women, and then obviously we see how that is translated into increased risks for different diseases. But then I would like to now maybe shift gears and go into the history and have a bit of a lesson, why. Why has it been that even though we have these really staggering numbers in terms of the prevalence for Alzheimer's disease, in terms of different risk profiles and how they manifest, but what is the actual root of the problem? Where do you think the issue has begun, and what was potentially the helping role of this act, which was published in 1993 by National Institute of Health, that kind of revitalised the research? So, could we revisit that time?

Professor Liisa Galea:

Well, first of all, I'd say that that National Institute of Health, 1993, that was just to include women in clinical trials as well as racial ethnic minorities because they noticed that there wasn't enough. The other thing about that that I think is really important that's often missed is that that's just for NIH funded clinical trials. Which it's about something, I can't quite remember if it's five or 15, but it's a pretty small proportion of clinical trials that are funded by NIH specifically.

So, the rest of the clinical trials do not have that mandate or law, depends on the country of which they are funded. So that's really important. Say for example, in Canada, we don't have that mandate. There's no mandate that you must add to clinical trials. There was a longstanding idea that maybe likely because we are thought of as baby making machines, our reproductive capabilities, that it was dangerous for us to be in clinical trials or for women to be in clinical trials, and we must preserve our reproduction.

But what's interesting about that is we still don't see a lack of women in clinical trials past reproductive age. So, I can't account for all of it, but that was sort of this idea. And then there was another idea that men and women, males and females don't really differ that much. Our physiology isn't very different except for our reproductive tracts, like our ovaries and our mammillary glands are a little bigger, but that's really the only difference. So, it didn't really matter. We didn't have to study females, because whatever we found in males is going to be exactly the same. And maybe to a certain extent that's true.

We know we both have two arms and two legs, two eyes for the most part. But we have to remember that biologically, I can speak more to the biology side, but certainly environment really matters as well. But our XX, XY, whatever sex hormone complement we have, is at every single cell in every single organ of our body, at least every nucleated cell. So those matter, and we're going to have different hormone receptors, particularly on those different organs. But I think it was just sort of a lack of thinking deeply about the fact that female physiology could be different.

Dr Maria Teresa Ferretti:

But if I may interject, Liisa, I think it's that, but I've been thinking a lot about this, what has been blocking us, why we haven't done more. And in my experience at least, I have encountered two blockers, something that maybe we can discuss together. One is the risk of something that is called neuro-sexism. You can't just say that the heart of a woman is different from the heart of a man, and most people will be okay with that when you present the evidence and the story ends there. But if you say that the brain of a woman is different from the brain of men-

Professor Liisa Galea:

I know people get mad. People get mad.

Dr Maria Teresa Ferretti:

Exactly. And the conversation becomes political, and you are manipulated, and these scientific evidence is used to support a neuro-sexist type of agenda. So, I feel many scientists just to avoid that.

Professor Liisa Galea:

Yes, they want to avoid it.

Dr Maria Teresa Ferretti:

Yeah, I think you have to-

Professor Liisa Galea:

What's the other barrier? I'm going to talk about that in a second. Yeah.

Dr Maria Teresa Ferretti:

The other one that I, again, by direct experience because it was actually a pushback that I personally received is related to feminism. So, the whole idea is that if you say that people are different, you are somehow detracting from the idea that we are equal and that we have equal rights. So, then you are not a real feminist if you're saying that people are different, and you're going against women's rights. And I've been spending a lot of time trying to convince people that if you really want to achieve... We have the same right, but it doesn't mean that we are the same. And to achieve the same right, we need to consider that we are different. So, it's the whole difference between equity and equality. So, I actually personally think that it's just only considering the differences between sexes and genders. We can truly implement health equity and really address the rights of women. But I have personally experienced this as a blocker. How about you?

Professor Liisa Galea:

I would just say, in fact, I kind of lumped those two together, neuro-sexism but I'm a feminist. But feminist means that you want equality and equity. It doesn't mean that you don't acknowledge that there might be some differences. What I find really interesting is from a neuro-sexism perspective, and it is absolutely out there, is that somehow a difference in the brain means that female brains are inferior. I don't see it that way. Why doesn't it mean that male brains are inferior? And actually, why is it inferiority, superiority question at all?

It's about there are some differences, let's figure out how that might contribute to either effective treatments or vulnerability to disease. And when we don't explore these, we are missing a huge part of the solution, and we can talk about that. I'd say even in heart health, I would say there is still an under-representation of women in clinical trials. So even there where we don't have a neuro-sexism, we still have that problem. So, I do also think there's a little bit of the patriarchy [inaudible 00:20:32] we don't know, but there's a reluctance I think to include, and maybe people think that it's adding a complication rather than cleaning up the data, if I may.

There have been a number of studies now looking at things like schizophrenia and asthma and looking at the genetic contributions of those and Alzheimer's disease as well, and when you add sex or gender as a factor, you actually could clean up the results quite a bit. And that might sound bad, but actually it's really fantastic to be able to say, just by including one variable in your analysis that you can make it clearer, how the disease might be progressing differently between these individuals. Because that's going to tell us, "Hey, we might need to intervene sooner or we need to intervene with this drug earlier," in one sex versus the other. As simple as just looking at whether sex makes a difference.

Dr Laura Stankeviciute:

I really love how this discussion is shaping itself as we go and just bringing also these political or more nuanced things that are not just the biology, but yeah, also if you're studying sex differences and advocating for women's health, you are like a feminist, and what do you feel like you are better or more superior? And feminism in itself, it's not superiority versus inferiority, but it is, as you said, it's about equality, and then women's health having its own right.

And then to be diagnosed by the symptoms that women express, not by the symptoms that the textbook were written for, which were written for male symptomatology, and then obviously getting the required treatment. And that kind of also leads me to this other topic where I think it has become really, really big in the past few years in our field, all the concept about personalised medicine and sex specific medicine. And sometimes I do feel like it has become a bit of a buzzword and maybe has lost a bit of a meaning because everything is now tagged as personalised for, but to whom? And what does it actually mean for the personalised medicine to be specific? And I know that Maria Teresa is your kind of forte. So, could you just give your perspective on what it is, and why do we hear this so much all the time from research to social media?

Dr Maria Teresa Ferretti:

No, Laura, I agree with you that this has become a buzzword, and we tend to use precision medicine, personalised medicine interchangeably. And the concepts are a little bit confused. When I started, and we were talking about precision medicine, everybody would just think about genetics. So, tailoring a treatment or care based on the genetic characteristics of a patient. And this is just one part of the story. So, I still think even though it's a buzzword, I still think it's super important, and I'm super passionate about it.

The definition that I give of precision medicine is the approach that allows us to give the right treatment to the right patient at the right time. So really tailoring whatever we are doing if it's a treatment, a prevention, whatever operation we're doing, but tailoring it on the characteristic of that specific patient, which is crucially important, especially in a disease that is so heterogeneous like Alzheimer's.

I really do think that a lot of delays have happened in the past because we have just put in the same pot population of patients that actually are different from a biological point of view. And for sure sex and gender are some of the drivers of all these differences and heterogeneity that we see. So, for me, precision medicine is really the future of medicine in general. And just to share something personal, I became even more convinced about this when I had a personal experience with breast cancer.

That's for me the gold standard of precision medicine because they really have very specific biomarkers. They took a biopsy. In two weeks, they knew exactly what type of tumour I was having in a matter of few more weeks. Like a month maybe, we had decided together based on all my imaging and blood biomarkers, what was the appropriate course of treatment. And in a couple of months, I had my surgery, and everything was done and it worked. It literally saved my life.

So why we can't have that in dementia myself, after going through all this, I reflected back and I said, "This, this, we should have this." Why patients still wait sometimes on average. In the literature it says, "Two years," to get a diagnosis of Alzheimer's. In my personal experience more than that. Why it takes so long? Why with treatments in neurology and psychiatry, we still go with trial and error. We try something, we see how it goes, and then if it doesn't work, then we move to something else.

This is for me, after seeing what precision medicine can deliver, this is just unacceptable. We must be able to do better. So, we must find ways to be more precise, to tailor treatments. And I think right now is the moment that this will become possible in neurology and in Alzheimer's because we're starting to have a biological definition of the disease, biomarkers for early diagnosis, new disease modifying treatment. So, I think now is the moment that we're starting to have the elements, the tools that then we will be able to organise according to a precision model approach. So maybe it wasn't so easy in the past years, but I think now we really have to push for it because we can definitely have tailored prevention, diagnosis and treatment based on individual characteristic.

And sex and gender are basically the foundation of this. If you want to give the right treatment to the right patient at the right time, if the patient is a man or a woman, it does make a huge difference, as Liisa said, for both biological and socioeconomic reasons. So, for me, it's just a given that this will need to be integrated in a precision medicine approach in Alzheimer's. I don't know if I'm too optimistic. I don't know. Liisa, what do you think?

Professor Liisa Galea:

I was going to say that I think that's spot on. I think that for breast cancer and prostate cancer, they've done really great stuff in the field. Breast cancer can occur in men, of course, but the majority of cases are in women. And I think maybe we're so far ahead in those fields and have great survival rates because of the fact that people had to include sex as a factor by necessity, they had to do it.

I would also say, as you said, "There's a delay in diagnosis." Erin Sundermann, who's a researcher in the US, has done some really fantastic work because women in general score higher on a variety of memory tests, of verbal memory, global cognition, executive function. That's partly how Alzheimer's disease and mild cognitive impairment, a prodromal state to Alzheimer's disease is diagnosed. And if people aren't using sex-specific norms, we're going to be missing women that are scoring higher.

And we might be over diagnosing men that are scoring lower, but they're just lower in general. And that's exactly what she found. She found that just by using sex as a factor, in retrospective data, she could clean up the data, clean up, and properly diagnose people in that prodromal state to Alzheimer's disease by 20%. She found 10% more females, 10% fewer males that were sort of incorrectly categorised. That's really important. And that if we don't include sex as a factor, we're going to miss those early biomarkers. The people that are looking at, there are some blood-based biomarkers right now that it shows some really fantastic promise, but if we're not using sex as a factor, we're going to miss the threshold.

And one other little thing I'll say is, "I've had some pushback about using sex as a part of precision medicine and personalised medicine because it is genetics," which I find funny because we still have XX and XY as part of it. But the other part is that these, we have to also consider within sex differences and within gender differences as well. So, we talked already about menopause, earlier age of menopause. Not all of us go through the same kinds of menopause. We have different kinds of menopause symptoms, age, symptoms, whether or not we're taking menopausal hormone therapy, what type we're taking in, when. All of this will shape probably our therapeutics; it shapes our brain specifically and needs to be considered in terms of precision medicine. So, I do agree we'll get there.

Dr Maria Teresa Ferretti:

Because you mentioned the early diagnosis piece, which I love, and I always quote Erin Sundermann work because I think it's really showing the potential and the next step. So, it's not just the diagnosis that we might be missing women in very early stages of and diagnosing them later. This is going to have a huge impact now that we're starting to have disease modifying treatment. Especially the amyloid based ones work better in the early stages. If we miss women in the early stages, these treatments are not going to work because we diagnose them too late. So, I really, really think that these are not just theoretical cases, these are differences that will impact the possibility of people to receive the proper treatment, at the proper time in their disease journey. So very, very important.

Professor Liisa Galea:

Yeah, and I would also just add the amyloid treatment. So there's also data that suggests that an amyloid is another one of the neuropathological features of Alzheimer's disease that it looks like, again, very little work, but there's some work from Jessica Caldwell showing, and also in some animal models we've looked at that females have more resilience in the face of a lot of amyloid.

So, they might not be showing the same kind of brain changes than a male will show, decreased hippocampal volume, for example, which is just a specific area in the brain. So, you might again be missing females at that stage because they're actually showing resilience. They might need a different kind of treatment at that time period. And that's stuff we're missing right now because we just don't have all the information we need.

Dr Laura Stankeviciute:

Yeah, I think that's really correct on your last point. And also, when we look at these clinical trials, we also see some differences in the way, like in the efficacy obviously of the drug for males and females. So, when we diagnose women earlier, we then also potentially need to work on slightly better dosages, different maybe paradigms as well. And just before we kind of move to another topic, I really appreciate Maria Teresa, your personal story. And obviously it's a different field, but I think we as Alzheimer's researchers, we have a lot to learn from others. So sometimes maybe it's not necessary to completely reinvent the wheel but actually base the practises from what's working. And obviously this biological staging is definitely going to help us a lot.

And thank you so much for being so open and sharing your personal lived experiences. And obviously we're now on the topic of Alzheimer's disease, but we know there are more differences when it comes to women's health in terms of autoimmune, psychiatric diseases, sleeve differences.

And we as researchers, we sometimes live in this tiny bubble where we feel that we know the numbers, but actually when we go out of the streets, outside laboratories and conferences, I still get so surprised, but that people don't understand of how big is this issue, and why do you think this is so, and what do we need to do in order to take the knowledge to the public and also to the clinical care because that's what we want at the end of the day. The personalised treatment should be provided for women, but what if the government doesn't know about it? And it just stays in our meetings and our conversations and our podcasts.

Dr Maria Teresa Ferretti:

First of all, Laura, something like this that we're doing today, a podcast, I think this is a huge contribution. I think more of this, please, we need this type of communication among experts and scientists, but also with the lay public and the policymakers. The more the better. It's highly needed. But in general, in brain health, I find.

I have two answers to your question. So why we have these numbers that are so impressive, why nobody's paying attention? One suspect that I have is that a lot of these diseases, we can mention migraine, there is depression. These are diseases that are highly stigmatised in general. So, I feel they overwhelmingly affect women, but they're also highly stigmatised. So, I think there is some resistance in the society to just talk about these diseases in general, and they're sometimes seen as weakness. There are some societal issues I find in just talking about these diseases in general and dementia, we don't even go there.

I mean the humongous amount of stigma that we have. So, it just sums on the fact that people are not paying attention to this sex and gender differences. But something that I'm very, very interested right now, and I'm trying to actively contribute, is the second part of your question. So, what can we do? Why is this not really translating into something at the clinical level that patients can benefit from? I'm also asking myself that because I feel like there is a lot of evidence right now. In some fields it's actually really substantial evidence. The example that I give all the time is actually from Parkinson's because I think the case there is even clearer of, for instance, side effects, way more side effects in dyskinesias with levodopa in women than men. And this is something that not all doctors know, and the doctors that are aware about it, they just kind of do trial and error, adjusting the dosing, right? There are no guidelines.

And this is something that is very well established in the literature. So, I asked myself why? Where is the problem? And I concluded that we are missing, there is this gap between the scientific evidence and the clinical implementation, and we need guidelines. So, we need to involve professional organisations, neurologists, and psychiatrists, to have them on board and to release guidelines so that doctors actually know what to do. They have not a script, but something to follow, right? An algorithm to follow.

So, something that I'm trying to contribute right now, I'm working with the European Academy of Neurology, and we have a coordinating panel on diversity, equity, and inclusion. So, this is the organisation of neurologists in Europe, and they're really interested in gender differences. So, we are starting this type of work in mapping how much sex and gender are already integrated in clinical guidelines and trying to understand why we don't have it more. And the answer that I'm receiving right now is that, yeah, everything Alzheimer, that the evidence that we have, yes, it's very strong, but it's not enough. You need higher quality evidence. You need randomised clinical trials; you need meta-analysis. So, I think at some point we just have to sit all together and just say, "What is the evidence that we need? What is a study that would convince you?" And we just run the study. That's what we need to do. I don't think it's impossible. We just need to do it.

Professor Liisa Galea:

Can I add to that and say, "I don't agree with what Maria Teresa said a hundred percent." I will also say, "We just don't have the study." So, there's two parts of the equation. We have the research, and we have the clinical, and I think in Canada we call that a second valley of death. So, it takes about 17 years to go from research to clinical practise and closing that gap is really important.

But the research itself, hardly anyone's doing it. So, we just looked at 15 years of research in Canada, the major funding agency, they are called Canadian Institute for Health and Sciences. And we looked at the top 10, 11 actually, burdens of disease for women including migraines, headache disorders, depression, anxiety, Alzheimer's disease and cardiovascular disease, and a number of others, musculoskeletal disorders. Two, well, it was 4% of research went over 15 years to studying specifically women or females with the top 11 [inaudible 00:36:28]

So, we just don't have, to your point about we need mice control trials and better ever, we just don't have the research. I don't think it's valid. I don't know. And this is part of my speculation, but it's not valued as much as it should be. And so, what I do think we need for change, is for governments and funders to actually specifically fund this type of research, because if it isn't specifically funded, people just don't do it on their own.

And researchers are like everyone else; we go to where the money is. And a very good success story for this I would say is HIV AIDS. Billions of dollars went into it from number of different countries, and it went from being a death sentence to being able to live with the disease and pretty much a full life now. It's a very complicated virus, but that's where we got by pouring research money into it. And that's what we're going to need for sex and gender science and women's health in general.

Dr Laura Stankeviciute:

Thank you so much for sharing this perspectives. And also, Maria Teresa, it's great that there are these efforts in Europe that are trying to move the needle and actually push for more sex-inclusive and gender-inclusive medicine. And I think what is also very interesting when we talk about obviously funding, and as an early career researcher, I face that on daily basis, and it is really difficult to write a grant. And when you're writing a grant that is not on, let's say, "Maybe the sexiest topics in the field," it just becomes pushed towards the bottom. But I do still feel like if we are really passionate and we see that this is the topic that requires a lot of attention and research interest, we have to just push.

And obviously that's not the topic of today, but I think researchers like you and a lot of younger researchers like me are looking up to you because of your careers. But I'm sure you had to fight a lot for the funding until you got where you are today. So maybe it's kind of a message-

Professor Liisa Galea:

Still fighting.

Dr Laura Stankeviciute:

... for all of us. Exactly. And maybe just kind of finishing up a little bit on more of the positive note in terms of what gives you hope in this field that we see still is not being researched enough, not enough of money are being poured in, but what gives you hope? What really helps you to get out of the bed in the morning and go and be super shining in the field with what you're doing? So, for both of you, maybe we can now switch the mic, so, Liisa, what is that thing that really sparks your hope?

Professor Liisa Galea:

It gives me hope is actually the conversation that's opening up to the public and early career researchers like you, people care. I was just at two things in Germany. It took me 12 days away from my bed and my home and my pets and my family, which was sometimes it's hard for us to do that, but it was gaining a lot of hope because they were both run by the younger generation. And one was about de-tabooing women's health, and how we can promote more women's and brain health in the future.

And the other one was, there was a summer school, but there were so many great young researchers that really cared and were really passionate about it. And so, I think it is really important for people like Maria Teresa and I, to still be standing here saying, "This is really important." I see-

Dr Laura Stankeviciute:

We need you standing all the time there.

Professor Liisa Galea:

Yes, we do. I know. It's true. The enthusiasm from the younger generation is great. And so, I do see the public opening up. It could just be my algorithm on my phone showing me what I want to see, but I think that does give me hope. I hope it translates into policy and guidelines.

Dr Maria Teresa Ferretti:

Yeah, Liisa, absolutely, a hundred percent. This is also my answer. I'm very busy, like everybody is. But whenever I'm invited to give a lecture or a workshop or anything with young researchers, early career residents, young doctors, I find the time, because first of all, because it's really worth it. And second, because it's so inspiring to interact with this new generation. Just to add on what you said, Liisa, thanks to the European Academy of Neurology, I had a few opportunities to work with residents. So, neurologists training, and these guys and girls are absolutely amazing.

And you know, Liisa, how the old guard, let's say that under the older generation of neurologists, they can be a little bit resistant to all this concept.

Professor Liisa Galea:

Yes, I know.

Dr Maria Teresa Ferretti:

But the young ones are really, really open, attentive, they are very sensitive to issues related to gender equity, health equity. They're really passionate about these things. Whenever I give lectures, I always have a couple of students come in later and asking me and really proposing projects or wanting to help.

So, there is a genuine, of course, it might be in our bubbles for sure, but I do see that there is a genuine interest in early career researchers and in neurologists and psychiatrists in training. And this gives me a lot of hope for the future because there are a big push and a genuine push of people that really believe this is important. And I think this is going to create a critical mass for change to happen.

Dr Laura Stankeviciute:

Well, I'm really hopeful that if this is coming from you and that the upcoming generation is going to continue and run with the torch that you have been leading for us for so many years. And I'm just checking the time, and I think it's ticking out.

Before we wrap up, I think it would be really nice to have a little bit of a tradition on this podcast so that we can remember and reflect a bit more on the personal level. So, I would like to start this from episode one with both of you, and I'll leave this just a very brief answer from both of you. So, what does woman's brain health mean to you? And if you can do it in one sentence, that would be fantastic.

Professor Liisa Galea:

I think it's going to be a long sentence. Maria Teresa, do you want to go first?

Dr Maria Teresa Ferretti:

Maybe if I can switch a little bit the question, Laura, I've been thinking about what I would really like people to understand about sex differences in the brain. If I had to think of one sentence, actually is quoting Liisa what she said earlier, but I really believe in it, that when we're talking about sex differences, different does not mean inferior. I really hope this message will stay with the audience. So, we shouldn't be afraid of studying differences. Actually, we should dig into them because by study them, that's exactly the way that we can implement health equity, gender equity, and by precision medicine. So different does not mean inferior.

Professor Liisa Galea:

Yeah, I was going to say something else, but maybe I'll jump off on that point and just say, "Diversity breeds discovery." So, we can learn a lot. That's true for your saving money for your pension. It's true for your workforce. That's true in research and understanding that there's diversity by sex and gender and within sexes and within genders. And that beautiful diversity brings beautiful discoveries, and that's the way forward.

Dr Laura Stankeviciute:

This was beautiful, both poetic, but also very, very strong message. So that's it for today's episode of XXplored. A huge thank you to both of the incredible speakers. It was such a pleasure to dive into these topics and try to explore a little bit together on this. And I'm sure there is much more coming out of your research, of your labs, but also from your advocacy roles that we will see in the upcoming years. And it's been me, Dr. Laura Stankeviciute, and you have been listening to XXplored Women's Brain Health on the Dementia Researcher podcast.

Voice Over:

Thank you for listening to XXplored Women's Brain Health podcast from Dementia Researcher. With generous support from the National Institute for Health and Care Research, Alzheimer's Association, Alzheimer's Research UK, Alzheimer's Society, and Race Against Dementia. From hormones to cognition, from risk to prevention, we feature conversations with researchers, clinicians, and change makers, working to challenge assumptions and close the gaps in how we understand and support the female brain.